2h or 3h-benzo[e]indazol-1-yl carbamate derivatives, the preparation and therapeutic use thereof

ABSTRACT

Compounds corresponding to the formula (I) 
     
       
         
         
             
             
         
       
     
     as defined in the disclosure, as well as methods for making such compounds, intermediates employed in such methods, pharmaceutical compositions containing the compounds of the invention, and methods of treatment using them.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/360,535, filed Jan. 27, 2009, now allowed, which is a continuation ofU.S. application Ser. No. 11/549,293, filed Oct. 13, 2006, now U.S. Pat.No. 7,501,449, which is a continuation of PCT/FR2005/001154, filed May10, 2005, which claims priority from FR Patent Application No. 04/05055,filed May 11, 2004.

SUMMARY OF THE INVENTION

A subject-matter of the invention is 2H— or 3H-benzo[e]indazol-1-ylcarbamate derivative compounds which exhibit an in vitro and in vivoaffinity for peripheral-type benzodiazepine receptors (PBR or p sites).

A first subject-matter of the invention is the compounds correspondingto the general formula (I) below.

Another subject-matter of the invention is processes for the preparationof the compounds of general formula (I).

Another subject-matter of the invention is the uses of the compounds ofgeneral formula (I), in particular in medicaments or in pharmaceuticalcompositions.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention correspond to the general formula (I):

in whichW represents an oxygen or sulphur atom;X₁, X₂, X₃ and X₄ each represent, independently of one another, ahydrogen or halogen atom or a cyano, C₁-C₆-alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy or C₁-C₆-fluoroalkoxy group;Y is in the (N2) or (N3) position;when Y is in the (N2) position, Y represents a C₁-C₆-alkyl,C₁-C₆-fluoroalkyl, aryl or heteroaryl group;when Y is in the (N3) position, Y represents an aryl or heteroarylgroup;the aryl or heteroaryl groups optionally being substituted by one ormore atoms or groups chosen from halogen atoms or C₁-C₆-alkyl,C₁-C₆alkoxy, C₁-C₆-alkylthio, C₁-C₆-alkyl-S(O)—, C₁-C₆-alkyl-S(O)₂— orC₁-C₆-fluoroalkyl groups;the bond in the C₄-C₅ position is a double or single bond;R₁ and R₂ each represent, independently of one another, an aryl, benzylor C₁-C₆-alkyl group; or else R₁ and R₂ form, with the nitrogen atomwhich carries them, a heterocycle optionally substituted by one or moreC₁-C₆-alkyl or benzyl groups.

In the context of the present invention:

C_(t)-C_(z) where t and z can take the values from 1 to 6, is understoodto mean a carbon chain which can have from t to z carbon atoms, forexample C₁₋₃, a carbon chain which can have from 1 to 3 carbon atoms;

an alkyl is understood to mean a saturated, linear or branched,aliphatic group. Mention may be made, by way of examples, of the methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl groups,and the like;

a fluoroalkyl is understood to mean an alkyl group, one or more hydrogenatoms of which have been substituted by a fluorine atom;

an alkoxy is understood to mean an —O-alkyl radical where the alkylgroup is as defined above;

a fluoroalkoxy is understood to mean an alkoxy group, one or morehydrogen atoms of which have been substituted by a fluorine atom;

an alkylthio is understood to mean an —S-alkyl radical where the alkylgroup is as defined above;

a heterocycle is understood to mean a 4- to 7-membered cyclic groupcomprising a nitrogen atom and optionally another heteroatom, such asnitrogen, oxygen or sulphur. Mention may be made, as examples ofheterocycles, of the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, azepinyl, piperazinyl or homopiperazinyl groups;

an aryl is understood to mean an aromatic cyclic group comprisingbetween 6 and 10 carbon atoms. Mention may be made, as examples of arylgroups, of the phenyl or naphthyl groups;

a heteroaryl is understood to mean a 5- or 6-membered aromatic cyclicgroup comprising 1 or 2 heteroatoms, such as nitrogen, oxygen orsulphur. Mention may be made, as examples of heteroaryl groups, of thepyridyl, thienyl, furyl, pyrimidinyl, pyrazinyl or pyridazinyl groups;

a member is understood to mean, in a cyclic group, an atom connected tothe two adjacent atoms of the ring;

a halogen atom is understood to mean a fluorine, a chlorine, a bromineor an iodine.

The compounds of general formula (I) can comprise one or more asymmetriccarbons. They can exist in the form of enantiomers or ofdiastereoisomers. These enantiomers and diastereoisomers, and theirmixtures, including the racemic mixtures, form part of the invention.

The compounds of formula (I) can exist in the form of bases or ofaddition salts with acids. Such addition salts form part of theinvention.

These salts are advantageously prepared with pharmaceutically acceptableacids but the salts of other acids, for example of use in thepurification or the isolation of the compounds of formula (I), also formpart of the invention.

The compounds of general formula (I) can exist in the form of hydratesor of solvates, namely in the form of combinations or associations withone or more molecules of water or with a solvent. Such hydrates andsolvates also form part of the invention.

Among the compounds of formula (I) which are subject-matters of theinvention, a first subgroup of compounds is composed of the compoundsfor which:

W represents an oxygen or sulphur atom; and/or X₁, X₂ and X₃ eachrepresent, independently of one another, a hydrogen atom, a halogenatom, more particularly a fluorine, chlorine or bromine atom, a cyanogroup, a C₁-C₆-alkyl group, more particularly a methyl group, or aC₁-C₆-alkoxy group, more particularly a methoxy group; and/orX₄ represents a hydrogen atom; and/orY is in the (N2) or (N3) position;when Y is in the (N2) position, Y represents a C₁-C₆-alkyl group, moreparticularly a methyl or ethyl group, a C₁-C₆-fluoroalkyl group, moreparticularly a trifluoroethyl group, an aryl group, more particularly aphenyl group, or a heteroaryl group, more particularly a pyridyl orpyrazinyl group;when Y is in the (N3) position, Y represents an aryl group, moreparticularly a phenyl group, or a heteroaryl group, more particularly apyridyl or pyrimidinyl group;the aryl or heteroaryl groups optionally being substituted by one ormore atoms or groups, more particularly by one or two atoms or groups,chosen from halogen atoms, more particularly fluorine or chlorine atoms,C₁-C₆-alkyl groups, more particularly methyl groups, and C₁-C₆-alkoxygroups, more particularly methoxy groups; and/orthe bond in the C4-C5 position is a double or single bond; and/orR₁ and R₂ each represent, independently of one another, an aryl group,more particularly a phenyl group, or a C₁-C₆-alkyl group, moreparticularly a methyl, ethyl, n-propyl, t-butyl or isopropyl group; orelse R₁ and R₂ form, with the nitrogen atom which carries them, aheterocycle, more particularly pyrrolidinyl, piperidinyl, morpholinyl orpiperazinyl, optionally substituted by one or two C₁-C₆-alkyl groups,more particularly methyl groups.

Among the compounds of formula (I) which are subject-matters of theinvention, a second subgroup of compounds is composed of the compoundsfor which:

W represents an oxygen or sulphur atom; and/or X₁, X₂ and X₃ eachrepresent, independently of one another, a hydrogen atom, a halogenatom, more particularly a fluorine, chlorine or bromine atom, aC₁-C₆-alkyl group, more particularly a methyl group, or a C₁-C₆-alkoxygroup, more particularly a methoxy group; and/orX₄ represents a hydrogen atom; and/orY is in the (N2) or (N3) position and represents an aryl group, moreparticularly a phenyl group, or a heteroaryl group, more particularly apyridyl, pyrazinyl or pyrimidinyl group;the aryl or heteroaryl groups optionally being substituted by one ormore atoms or groups, more particularly by one or two atoms or groups,chosen from halogen atoms, more particularly fluorine or chlorine atoms,C₁-C₆-alkyl groups, more particularly methyl groups, and C₁-C₆-alkoxygroups, more particularly methoxy groups; and/orthe bond in the C4-C5 position is a double or single bond; and/orR₁ and R₂ each represent, independently of one another, an aryl group,more particularly a phenyl group, or a C₁-C₆-alkyl group, moreparticularly a methyl, ethyl, n-propyl, t-butyl or isopropyl group; orelse R₁ and R₂ form, with the nitrogen atom which carries them, aheterocycle, more particularly pyrrolidinyl, piperidinyl, morpholinyl orpiperazinyl, optionally substituted by one or two C₁-C₆-alkyl groups,more particularly methyl groups.

Among the compounds of formula (I) which are subject-matters of theinvention, a third subgroup of compounds is composed of the compoundsfor which:

W represents an oxygen or sulphur atom; and/or X₁, X₂ and X₃ eachrepresent, independently of one another, a hydrogen atom, a halogenatom, more particularly a fluorine, chlorine or bromine atom, aC₁-C₆-alkyl group, more particularly a methyl group, or a C₁-C₆-alkoxygroup, more particularly a methoxy group; and/orX₄ represents a hydrogen atom; and/orY is in the (N3) position and represents an aryl group, moreparticularly a phenyl group, or a heteroaryl group, more particularly apyridyl or pyrimidinyl group;the aryl or heteroaryl groups optionally being substituted by one ormore atoms or groups, more particularly by one or two atoms or groups,chosen from halogen atoms, more particularly fluorine or chlorine atoms,C₁-C₆-alkyl groups, more particularly methyl groups, and C₁-C₆-alkoxygroups, more particularly methoxy groups; and/orthe bond in the C4-C5 position is a double or single bond; and/orR₁ and R₂ each represent, independently of one another, an aryl group,more particularly a phenyl group, or a C₁-C₆-alkyl group, moreparticularly a methyl, ethyl, t-butyl or isopropyl group; or else R₁ andR₂ form, with the nitrogen atom which carries them, a heterocycle, moreparticularly piperidinyl, optionally substituted by one or twoC₁-C₆-alkyl groups, more particularly methyl groups.

The compounds of general formula (I) can be prepared by the processesillustrated in the following schemes.

According to a first preparation route (Scheme 1), a compound of generalformula (II), in which X₁, X₂, X₃ and X₄ are as defined in the generalformula (I), is reacted with methyl carbonate in the presence of acatalytic amount of a base, such as sodium methoxide or sodium hydride,to obtain the ketoester of general formula (III). The condensation ofthe ketoester (III) with hydrazine, for example in a polar solvent, suchas DMF or acetic acid, makes it possible to isolate the pyrazole ofgeneral formula (IV). The latter is subsequently N-substitutednonselectively by the action of an aryl or heteroaryl halide of generalformula Y-hal, in which Y is as defined in the general formula (I) andhal is a halogen atom, such as an iodine or a bromine, in the presenceof a base, such as potassium or caesium carbonate, or of potassiumtriphosphate, of a catalytic amount of a copper salt and of a diamine(S. L. Buchwald, J. Am. Chem. Soc., 2001, 123, 7727).

The resulting mixture composed of the positional isomers of generalformulae (Va) and (Vb), in which the Y group is respectively in the2-position and in the 3-position of the pyrazole ring, is subsequentlyderivatized by the action of a carbamoyl chloride derivative of generalformula ClC(W)NR₁R₂, in which W, R₁ and R₂ are as defined in the generalformula (I), in the presence of a base, such as potassium carbonate,sodium hydride or triethylamine, to obtain the carbamates of generalformulae (Ia) and (Ib), which are separated, at this stage, by methodsknown to a person skilled in the art, such as chromatography on a silicacolumn.

Alternatively, a second preparation route makes it possible to preparethe compounds of general formula (Ia) (Scheme 2).

It consists in condensing the ketoester of general formula (III), asdefined above, with a hydrazine of general formula Y—NH—NH₂, in which Yis as defined in the general formula (I), for example in a polarsolvent, such as DMF or acetic acid, and makes it possible to isolatethe pyrazole of general formula (Va), as defined above. The latter issubsequently acylated by the action of a carbamoyl chloride derivativeof general formula ClC(W)NR₁R₂, as defined above, in the presence of abase, such as potassium carbonate, sodium hydride or triethylamine, toobtain the carbamate of general formula (Ia).

The single bond in the C4-C5 position of the compounds of generalformula (I) can optionally be dehydrogenated to form a double bondaccording to a method known to a person skilled in the art, for exampleby analogy with the method described by Kozo, Shishido et al.,Tetrahedron, 1989, 45, 18, 5791-5804.

Alternatively, the compounds of general formula (I) comprising a singlebond in the C4-C5 position can be dehydrogenated by reaction with ahalogenating agent, such as N-bromosuccinimide, in the presence of aninitiator, such as 2,2′-azobis(2-methylpropionitrile). Under theseconditions, the compound of general formula (I) comprising a single bondin the C4-C5 position is first halogenated and then the resultingintermediate is subjected to an elimination reaction to result in thecompound (I) comprising a double bond in the C4-C5 position.

In Schemes 1 and 2, the reactants, when their method of preparation isnot described, are commercially available or are described in theliterature or else can be prepared according to methods which aredescribed therein or which are known to a person skilled in the art.

The compounds of general formula (II) can be obtained from commercialsources or can be prepared using methods described in the literature(Sims, J. J. et al., Tetrahedron Lett., 1971, 951).

Another subject-matter of the invention, according to another of itsaspects, is the compounds of formulae (Va) and (Vb). These compounds maybe of use as intermediates in the synthesis of the compounds of formula(I).

The chemical structures and the physical properties of a few compoundsof general formulae (Va) and (Vb) of the invention are illustrated inthe following Table 1. The melting points of the products are given inthe “M.p.” column.

TABLE 1 (Vb) or (Va)

No. X₁ X₂ X₃ X₄ Y M.p. (° C.) Va. 1 H H H H 2-(4-methylphenyl) 221-222Vb. 1 H Me H H 3-(pyrid-4-yl) 315-316 Va. 2 H F H H 2-(4-fluorophenyl)220-221 Vb. 2 H Cl H H 3-(pyrid-4-yl) 336-342 Va. 3 H Cl H H2-(pyrid-4-yl) 190-216

The preparation of some compounds in accordance with the invention isdescribed in the following examples. These examples are not limiting andonly illustrate the present invention. The numbers of the compoundsexemplified refer to those given in Tables 1 and 2. The elementalmicroanalyses, the LC-MS (liquid chromatography coupled to massspectrometry) analyses and the IR and NMR spectra confirm the structuresof the compounds obtained.

Example 1 Compound No. 17-Fluoro-2-(4-fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate 1.1 Methyl6-fluoro-2-hydroxy-3,4-dihydro-1-naphthoate

12.66 g (316 mmol) of 60% sodium hydride in oil, 900 ml of toluene and17.69 ml (210 mmol) of dimethyl carbonate are introduced into a 2 lreactor. The reaction mixture is stirred at reflux for 1 h. A solutionof 19 g (115 mmol) of 6-fluoro-3,4-dihydro-1H-naphthalen-2-one in 350 mlof toluene is subsequently added. The reaction mixture is heated atreflux for 24 h. The reaction mixture is subsequently cooled to 0° C.and then acidified by addition of 114 ml of acetic acid. 114 ml of waterare added and the separated organic phase is separated by settling andwashed with two times 150 ml of water and then with 100 ml of asaturated aqueous sodium chloride solution. The organic phase issubsequently dried over magnesium sulphate and then concentrated underreduced pressure to result in 26.1 g of a product which is used as is inthe following stage.

1.27-Fluoro-2-(4-fluorophenyl)-1-hydroxy-4,5-dihydro-2H-benzo[e]indazole(Va.2)

2 g (9 mmol) of the product obtained in Stage 1.1 and 2.73 g (16.8 mmol)of 4-fluorophenylhydrazine hydrochloride are introduced into a 100 mlreactor. The mixture is dissolved in 100 ml of acetic acid and heated atreflux for 4 h. The reaction mixture is subsequently cooled and thenconcentrated under reduced pressure. The residue is taken up in 150 mlof ethyl acetate and 100 ml of water. The organic phase is separated bysettling and washed twice with 100 ml of water and then once with 100 mlof a saturated aqueous sodium chloride solution. The organic phase issubsequently dried over magnesium sulphate and then concentrated underreduced pressure to result in 3.5 g of the expected compound.

Melting point: 220-221° C.

¹H NMR (d₆-DMSO): δ (ppm): 2.72 (d×d, 2H), 2.95 (d×d, 2H), 7.01 (m, 2H),7.3 (m, 2H), 7.75 (m, 3H).

1.3 7-Fluoro-2-(4-fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate (Compound No. 1)

3.5 g (9 mmol) of the product obtained in Stage 1.2, 3.48 g (25 mmol) ofpotassium carbonate and 2.66 ml (21 mmol) of N,N-diethylcarbamoylchloride are introduced into a 500 ml reactor. The reaction mixture isheated at reflux for 24 h and is then concentrated under reducedpressure. The resulting product is taken up in 100 ml of ethyl acetate.The organic phase is washed twice with 100 ml of water and then oncewith 100 ml of a saturated aqueous sodium chloride solution. The organicphase is subsequently dried over magnesium sulphate and thenconcentrated under reduced pressure to result in 5.96 g of crudeproduct. The mixture is purified by chromatography on a silica column,elution being carried out with a mixture of cyclohexane and ethylacetate. 2.2 g of the expected product are thus isolated andrecrystallized from isopropanol to produce 1.5 g (3.77 mmol) of thefinal product.

Melting point: 141-142° C.

¹H NMR (CDCl₃): δ (ppm): 1.95 (t, 3H), 2.6 (t, 3H), 2.97 (t, 2H), 3.98(t, 2H), 3.4 (q, 2H), 3.52 (q, 2H), 7.00 (m, 2H), 7.2 (m, 2H), 7.32 (m,1H), 7.56 (m, 2H).

Example 2 Compound No. 27-Fluoro-2-(4-fluorophenyl)-2H-benzo[e]indazol-1-yl N,N-diethylcarbamate

A solution of 0.7 g (1.76 mmol) of7-fluoro-2-(4-fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate, obtained in Stage 1.3 of Example 1, and of 1.2 g(5.2 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 25 ml oftoluene is stirred at reflux for 2 h and then cooled. The mixture ispoured onto 100 ml of ethyl acetate. This organic phase is washed withtwo times 100 ml of a saturated aqueous sodium hydrogencarbonatesolution, with 100 ml of water and then with 100 ml of a saturatedaqueous sodium chloride solution. The organic phase is separated bysettling, then dried over magnesium sulphate and concentrated underreduced pressure. After purification by chromatography on a silicacolumn (eluent: mixture of methylene chloride and of ethyl acetate) andrecrystallization from isopropanol, 500 mg (1.26 mmol) of the expectedproduct are obtained.

Melting point: 159-160° C.

¹H NMR (d₆-DMSO): δ (ppm): 1.04 (t, 3H), 1.21 (t, 3H), 3.28 (q, 2H),3.55 (q, 2H), 7.45 (m, 3H), 7.7 (m, 5H), 7.9 (d×d, 1H).

Example 3 Compounds Nos 3 and 47-Chloro-2-(pyrid-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride (Compound No. 3) and7-chloro-3-(pyrid-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride (Compound No. 4) 3.1 Methyl6-chloro-2-hydroxy-3,4-dihydro-1-naphthoate

10.1 g (252 mmol) of 60% sodium hydride in oil, 621 ml of toluene and14.18 ml (163 mmol) of dimethyl carbonate are introduced into a 2 lreactor. The reaction mixture is stirred at reflux for 1 h. A solutionof 15.2 g (84 mmol) of 6-chloro-3,4-dihydro-1H-naphthalen-2-one in 268ml of toluene is subsequently added. The reaction mixture is heated atreflux for 24 h. The reaction mixture is subsequently cooled to 0° C.and then acidified by addition of 92 ml of acetic acid. 114 ml of waterare added and the separated organic phase is separated by settling andwashed with three times 150 ml of water and then with 100 ml of asaturated aqueous sodium chloride solution. The organic phase issubsequently dried over magnesium sulphate and then concentrated underreduced pressure. The residue is purified by chromatography on a silicacolumn (elution being carried out with a mixture of cyclohexane and ofdichloromethane) to result in 12.8 g (53.6 mmol) of the expected productused as is in the following stage.

3.2 7-Chloro-1-hydroxy-4,5-dihydro-2H-benzo[e]indazole

28 g (117 mmol) of the product obtained in Stage 3.1 and 28.6 ml (586.6mmol) of hydrazine monohydrate are introduced into a 2 l reactor. Themixture is dissolved in 782 ml of acetic acid and heated at reflux for 4h. The reaction mixture is subsequently cooled and then concentratedunder reduced pressure. The resulting product is taken up in 300 ml ofethyl acetate and 300 ml of water. The organic phase is separated bysettling and washed twice with 200 ml of water and then once with 200 mlof a saturated aqueous sodium chloride solution. The organic phase issubsequently dried over magnesium sulphate and then concentrated underreduced pressure. The residue obtained is triturated from 200 ml ofethyl ether and then filtered off to result in 25 g (113.3 mol) of theexpected product.

Melting point: 232-233° C.

3.3 7-Chloro-1-hydroxy-2-(pyrid-4-yl)-4,5-dihydro-2H-benzo[e]indazoleand 7-chloro-1-hydroxy-3-(pyrid-4-yl)-4,5-dihydro-3H-benzo[e]indazole

15.2 g (68.8 mmol) of the product obtained in Stage 3.2, 16.95 g (82.66mmol) of 4-iodopyridine, 4.14 ml (34.44 mmol) oftrans-1,2-diaminocyclohexane, 1.31 g (6.89 mmol) of copper iodide and36.55 g (172.2 mmol) of potassium phosphate are introduced under aninert atmosphere into a 2 l reactor. The reaction mixture is suspendedin 690 ml of dioxane, brought to reflux for 24 h and then cooled. Themixture is concentrated under reduced pressure and then taken up in 200ml of water. This aqueous phase is acidified to pH 5 by successiveadditions of acetic acid. The suspension is stirred for 30 minutes andthen the precipitate obtained is filtered off, washed with water andthen dried under reduced pressure to produce 16.6 g (55.7 mmol) of theexpected N-arylation product in the form of a mixture of isomers.

LC-MS: 2 peaks at 60.4% and 38% corresponding to [MH]⁺=298.

3.4 7-Chloro-2-(pyrid-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride (Compound No. 3) and7-chloro-3-(pyrid-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride (Compound No. 4)

13 g (43.66 mmol) of the mixture of isomers obtained in Stage 3.3, 18.1g (131 mmol) of finely ground potassium carbonate and 11.07 ml (87.32mmol) of N,N-diethylcarbamoyl chloride are introduced, under an inertatmosphere, into a 2 l reactor. The reaction mixture is suspended in 1 lof acetonitrile, brought to reflux for 24 h and then cooled. Thereaction mixture is concentrated under reduced pressure. The resultingproduct is taken up in 300 ml of ethyl acetate and 300 ml of water. Theorganic phase is separated by settling and washed twice with 200 ml ofwater and once with 200 ml of a saturated aqueous sodium chloridesolution. The organic phase is subsequently dried over magnesiumsulphate and then concentrated under reduced pressure. The resultingproduct comprises the two positional isomers (Compounds Nos 3 and 4).The latter are separated by column chromatography (300 g of Merck 15-40microns silica, eluents: mixture of heptane and of ethyl acetate).

7-Chloro-2-(pyrid-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride (Compound No. 3)

Product No. 3, thus isolated, is converted to the hydrochloride bydissolving in a 0.1N solution of hydrochloric acid in isopropanol. Thesolution is concentrated to dryness under reduced pressure. Aftertriturating from ethyl ether, filtering and drying under reducedpressure, 2.3 g (5.79 mmol) of the final product are obtained.

Melting point: 250-251° C.

¹H NMR (d₆-DMSO): δ (ppm): 1.08 (t, 3H), 1.31 (t, 3H), 2.98 (m, 4H), 3.3(q, 2H), 3.68 (q, 3H), 7.27 (d, 1H), 7.38 (d×d, 1H), 7.46 (d×d, 1H),7.92 (d, 2H), 8.87 (d, 2H).

7-Chloro-3-(pyrid-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride (Compound No. 4)

Product No. 4, thus isolated, is converted to the hydrochloride bydissolving in a 0.1N solution of hydrochloric acid in isopropanol. Thesolution is concentrated to dryness under reduced pressure. Aftertriturating from ethyl ether, filtering and drying under reducedpressure, 6.2 g (15.62 mmol) of the final product are obtained.

Melting point: 224-226° C.

¹H NMR (d₆-DMSO): δ (ppm): 1.18 (t, 3H), 1.29 (t, 3H), 3.02 (t, 2H),3.31 (m, 4H), 3.51 (q, 2H), 7.20 (d, 1H), 7.32 (d×d, 1H), 7.45 (d, 1H),8.08 (d, 2H), 8.98 (d, 2H).

Example 4 Compound No. 58-Methoxy-3-(pyrid-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride 4.1 Methyl6-methoxy-2-hydroxy-3,4-dihydro-1-naphthoate

3.4 g (85.12 mmol) of 60% sodium hydride in oil, 180 ml of toluene and4.78 ml (56.75 mmol) of dimethyl carbonate are introduced into a 1 lreactor. The reaction mixture is stirred at reflux for 1 h. A solutionof 5 g (28.37 mmol) of 7-methoxy-3,4-dihydro-1H-naphthalen-2-one in 100ml of toluene is subsequently added. The reaction mixture is heated atreflux for 24 h. The reaction mixture is subsequently cooled to 0° C.and then acidified by addition of 30 ml of acetic acid. 30 ml of waterare added and the separated organic phase is separated by settling andwashed with two times 50 ml of water and then with 50 ml of a saturatedaqueous sodium chloride solution. The organic phase is subsequentlydried over magnesium sulphate and then concentrated under reducedpressure. After purification by chromatography on a silica column(eluent: mixture of methylene chloride and of heptane), 3.9 g (16.64mmol) of the expected product are obtained and are used as in thefollowing stage.

4.2 1-Hydroxy-8-methoxy-4,5-dihydro-2H-benzo[e]indazole

3.9 g (16.65 mmol) of the product obtained in Stage 4.1 and 4.06 ml(83.24 mmol) of hydrazine monohydrate are introduced into a 0.5 lreactor. The mixture is dissolved in 166 ml of acetic acid and heated atreflux for 4 h. The reaction mixture is subsequently cooled and thenconcentrated under reduced pressure. The resulting product is taken upin 100 ml of ethyl acetate and 100 ml of water. The organic phase isseparated by settling and washed twice with 100 ml of water and thenonce with 100 ml of a saturated aqueous sodium chloride solution. Theorganic phase is subsequently dried over magnesium sulphate and thenconcentrated under reduced pressure. The residue obtained is trituratedfrom 50 ml of ethyl ether and then filtered off to result in 2.4 g (11.1mmol) of the expected product.

4.3 1-Hydroxy-8-methoxy-3-(pyrid-4-yl)-4,5-dihydro-3H-benzo[e]indazole

1.2 g (5.55 mmol) of the product obtained in Stage 4.2, 1.36 g (6.66mmol) of 4-iodopyridine, 0.33 ml (2.77 mmol) oftrans-1,2-diaminocyclohexane, 0.105 g (0.55 mmol) of copper iodide and2.94 g (13.87 mmol) of potassium phosphate are introduced, under aninert atmosphere, into a 0.1 l reactor. The reaction mixture issuspended in 55 ml of dioxane, brought to reflux for 24 h and thencooled. The mixture is subsequently taken up in 1 l of a 1/1 mixture ofwater and of ethyl acetate. The organic phase is separated by settlingand then washed with water (50 ml). This aqueous phase is acidified topH 5 by successive additions of acetic acid. The precipitate obtained isfiltered off, washed with water and then dried under reduced pressure toproduce 0.2 g (0.68 mmol) of the expected N-arylation product. Theorganic phase is dried over magnesium sulphate and then concentratedunder reduced pressure. The resulting product is purified bychromatography on a silica column (eluents: mixture of dichloromethaneand methanol) to produce an additional 0.57 g (1.94 mmol) of theexpected N-arylation product.

¹H NMR (d₆-DMSO): δ (ppm): 2.89 (d×d, 2H), 3.09 (d×d, 2H), 3.73 (s, 3H),6.2 (d×d, 1H), 7.1 (m, 2H), 7.48 (m, 2H), 8.6 (m, 2H).

4.4 8-Methoxy-3-(pyrid-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride (Compound No. 5)

0.77 g (2.63 mmol) of the product obtained in Stage 4.3, 1.09 g (7.88mmol) of finely ground potassium carbonate and 0.67 ml (5.25 mmol) ofN,N-diethylcarbamoyl chloride are introduced, under an inert atmosphere,into a 0.1 l reactor. The reaction mixture is suspended in 30 ml ofacetonitrile, brought to reflux for 24 h and then cooled. The reactionmixture is concentrated under reduced pressure. The resulting product istaken up in 100 ml of ethyl acetate and 100 ml of water. The organicphase is separated by settling and washed twice with 50 ml of water andthen once with 50 ml of a saturated aqueous sodium chloride solution.The organic phase is subsequently dried over magnesium sulphate and thenconcentrated under reduced pressure. The resulting product is purifiedby column chromatography (90 g of Merck 15-40 microns silica, eluents:mixture of heptane and of ethyl acetate). The compound thus isolated isrecrystallized from isopropanol and then redissolved in a 0.1N solutionof hydrochloric acid in isopropanol. The solution is concentrated todryness under reduced pressure. After triturating from ethyl ether,filtering off and drying under reduced pressure, 234 mg (0.59 mmol) ofthe expected compound are obtained.

Melting point: 225-227° C.

¹H NMR (d₆-DMSO): δ (ppm): 1.15 (t, 3H), 1.3 (t, 3H), 2.92 (t, 2H),3.2-3.4 (m, 4H), 3.51 (q, 2H), 3.71 (s, 3H), 6.8 (m, 2H), 7.2 (d, 1H),7.98 (d, 2H), 8.82 (d, 2H).

Example 5 Compound No. 827-Chloro-4,5-dihydro-3-(pyrid-4-yl)-3H-benzo[e]indazol-1-ylN,N-diisopropylcarbamate hydrochloride

2.3 g (7.72 mmol) of the mixture of isomers obtained in Stage 3.3 ofExample 3, in solution in 30 ml of dimethylformamide, are addeddropwise, under an inert atmosphere and at 0° C., to a suspension of 0.4g (10.04 mmol) of sodium hydride in 17 ml of dimethylformamide in a 1 lreactor. After stirring at ambient temperature for 1 hour, 1.39 g (8.5mmol) of N,N-diisopropylcarbamoyl chloride in 30 ml of dimethylformamideare added dropwise. The reaction mixture is stirred at ambienttemperature for 18 h and is then concentrated under reduced pressure.The resulting product is taken up in 300 ml of ethyl acetate and 300 mlof water. The aqueous phase is brought to pH 5 by addition of aceticacid. The organic phase is separated by settling and washed twice with200 ml of water and then once with 200 ml of a saturated aqueous sodiumchloride solution. The organic phase is subsequently dried overmagnesium sulphate and then concentrated under reduced pressure. Theresulting product is purified by column chromatography (300 g of Merck15-40 microns silica, eluents: mixture of dichloromethane and of ethylacetate). The product thus isolated is converted to the hydrochloride bydissolution in a 0.1N solution of hydrochloric acid in isopropanol. Thesolution is concentrated to dryness under reduced pressure. Aftertriturating from ethyl ether, filtering off and drying under reducedpressure, 1.2 g (2.6 mmol) of the final product are obtained.

Melting point: 237-269° C.

¹H NMR (d₆-DMSO): δ (ppm): 1.29 (m, 12H), 3.02 (m, 2H), 3.19 (m, 2H),3.91 (m, 1H), 4.2 (m, 1H), 7.2 (d, 1H), 7.35 (d×d, 1H), 7.42 (s, 1H),7.6 (d, 2H), 8.7 (d, 2H).

Example 6 Compound No. 847-Chloro-3-(pyrid-4-yl)-3H-benzo[e]indazol-1-yl N,N-diisopropylcarbamatehydrochloride

1.65 g (3.38 mmol) of7-chloro-4,5-dihydro-3-(pyrid-4-yl)-3H-benzo[e]indazol-1-ylN,N-diisopropyl-carbamate, prepared according to the method described inExample 5, 1.105 g (6.21 mmol) of N-bromosuccinimide and 0.127 g (0.78mmol) of 2,2′-azobis(2-methylpropionitrile) are added to a 100 mlreactor. The mixture, dissolved in 40 ml of carbon tetrachloride, isstirred at reflux for 24 h and is then concentrated under reducedpressure. The resulting product is taken up in 300 ml of dichloromethaneand 2 ml of a concentrated aqueous ammonia solution. The organic phaseis separated and washed with 200 ml of water and then with 200 ml of asaturated aqueous sodium chloride solution. The organic phase issubsequently dried over magnesium sulphate and then concentrated underreduced pressure. The resulting product is purified by chromatography onan alumina column (eluents: mixture of dichloromethane and of methanol)and then on a silica column (eluents: mixture of dichloromethane and ofethyl acetate). The product thus isolated is converted to thehydrochloride by dissolution in a 0.1N solution of hydrochloric acid inisopropanol. The solution is concentrated to dryness under reducedpressure. After triturating from ethyl ether, filtering off and dryingunder reduced pressure, 1.2 g (2.6 mmol) of the final product areobtained.

Melting point: 234-248° C.

¹H NMR (d₆-DMSO): δ (ppm): 1.42 (m, 12H), 4.02 (m, 1H), 4.41 (m, 1H),7.6 (d×d, 1H), 7.8 (m, 3H), 7.92 (d, 2H), 8.15 (d, 1H), 8.79 (d, 2H).

The chemical structures and the physical properties of a few compoundsof general formula (I) according to the invention are illustrated in thefollowing Table 2.

In the “Salt” column of this table, “HCl” denotes a hydrochloride and“—” denotes a compound in the base state. The base:acid molar ratios areshown opposite. The “M.p.” column gives the melting points of theproducts, the amorphous compounds being characterized by their massspectrometry (MS) analytical results.

TABLE 2 (I)

C4-C5 M.p. No. X₁ X₂ X₃ X₄ W NR₁R₂ bond Y Salt (° C.) 1 H F H H ON(CH₂CH₃)₂ single 2-(4-fluorophenyl) — 141- 142 2 H F H H O N(CH₂CH₃)₂double 2-(4-fluorophenyl) — 159- 160 3 H Cl H H O N(CH₂CH₃)₂ single2-(pyrid-4-yl) HCl 250- 1:1 251 4 H Cl H H O N(CH₂CH₃)₂ single3-(pyrid-4-yl) HCl 224- 1:1 226 5 H H OCH₃ H O N(CH₂CH₃)₂ single3-(pyrid-4-yl) HCl 225- 1:1 227 6 H H H H O N(CH₃)₂ single2-(4-methylphenyl) — 130- 131 7 H H H H O N(CH₂CH₃)₂ single2-(4-chlorophenyl) — 148- 149 8 H H H H O

single 2-(3-chlorophenyl) — 150- 151 9 H H H H O N(CH₃)₂ single2-(3-chlorophenyl) — 128- 129 10 H H H H O N(CH₂CH₃)₂ single2-(3-chlorophenyl) — 111- 113 11 H H H H O

single 2-(3-chlorophenyl) — 155- 157 12 H H H H O N(CH(CH₃)₂)₂ single2-(3-chlorophenyl) — 116- 118 13 H H H H O N(CH₂CH₃)₂ single 2-phenyl —124- 125 14 H Cl H H O N(CH₂CH₃)₂ single 2-phenyl — 114- 116 15 H H H HO N(CH₃)Ph single 2-(3-chlorophenyl) — 75- 78 16 H H H H O N(CH₂CH₃)₂single 2-(2-chlorophenyl) — 396* 17 H H H H O N(CH₂CH₃)₂ single 2-ethyl— 60- 61 18 H H H H O N(CH₃)Ph single 2-ethyl — 348* 19 H H H H ON(CH₃)Ph single 2-(2,2,2- — 402* trifluoroethyl) 20 H H H H O N(CH₂CH₃)₂single 2-(4-fluorophenyl) — 132- 133 21 H H H H O N(CH(CH₃)₂)₂ single2-(4-fluorophenyl) — 95- 96 22 H H H H O N(CH₃)Ph single2-(4-fluorophenyl) — 197- 198 23 H H H H O

single 2-(4-fluorophenyl) — 211- 212 24 H H H H O

single 2-(4-fluorophenyl) — 174- 175 25 H H H H O

single 2-(4-fluorophenyl) — 175- 176 26 H H H H O N(CH₃)₂ single2-(4-chlorophenyl) — 211- 212 27 H H H H O N(CH(CH₃)₂)₂ single2-(4-chlorophenyl) — 203- 204 28 H H H H O N(CH₃)Ph single2-(4-chlorophenyl) — 202- 203 29 H H H H O

single 2-(4-chlorophenyl) — 212- 213 30 H H H H O

single 2-(4-chlorophenyl) — 200- 201 31 H H H H O

single 2-(4-chlorophenyl) — 185- 186 32 H H H H O

single 2-(4-chlorophenyl) — 157- 158 33 H H H H O N(CH₃)₂ single2-(4-fluorophenyl) — 216- 217 34 H H H H O

single 2-(4-fluorophenyl) — 167- 168 35 H H H H O N(CH₃)₂ single2-phenyl — 158- 159 36 H H H H O N(CH(CH₃)₂)₂ single 2-phenyl — 146- 14737 H H H H O N(CH₃)Ph single 2-phenyl — 169- 170 38 H H H H O

single 2-phenyl — 176- 177 39 H Cl H H O N(CH₂CH₃)₂ single2-(4-fluorophenyl) — 155- 156 40 H H H H O N(CH₃)(CH₂)₂CH₃ single2-(4-fluorophenyl) — 143- 144 41 H H H H O N(CH₂CH₃)₂ single2-(3-chloro-4- — 99- methylphenyl 101 42 H H H H O N(CH₂CH₃)₂ single2-(3-chloro-4- — 148- fluorophenyl) 150 43 H Cl H H O N(CH₂CH₃)₂ single2-(3-chloro-4- — 131- methylphenyl) 133 44 H Cl H H O N(CH₂CH₃)₂ single2-(2,4- — 78- difluorophenyl) 80 45 H H H H O N(CH₂CH₃)₂ single2-(pyrid-4-yl) HCl 298- 1:1 299 46 H Cl H H O N(CH₂CH₃)₂ single2-(pyrid-2-yl) — 108- 110 47 H OCH₃ H H O N(CH₂CH₃)₂ single2-(4-fluorophenyl) — 161- 162 48 H Br H H O N(CH₂CH₃)₂ single2-(4-fluorophenyl) — 162- 163 49 H Cl H H O N(CH₂CH₃)₂ single2-(3-chloro-4- — 108- fluorophenyl) 110 50 H Cl H H O N(CH₂CH₃)₂ single2-methyl — 117- 118 51 H H H H O N(CH₂CH₃)₂ double 2-(3-chlorophenyl) —125- 126 52 H H H H O N(CH₂CH₃)₂ double 2-(4-fluorophenyl) — 125- 126 53H H H H O N(CH₃)(CH₂)₂CH₃ double 2-(4-fluorophenyl) — 154- 155 54 H H HH O N(CH₂CH₃)₂ double 2-(3-chloro-4- — 412* fluorophenyl) 55 H H H H ON(CH₂CH₃)₂ double 2-(3-chloro-4- — 118- methylphenyl) 120 56 H Cl H H ON(CH₂CH₃)₂ double 2-(4-fluorophenyl) — 151- 153 57 H Cl H H O N(CH₂CH₃)₂double 2-(3-chloro-4- — 141- fluorophenyl) 143 58 H Cl H H O N(CH₂CH₃)₂double 2-(3-chloro-4- — 141- methylphenyl) 143 59 H Cl H H O N(CH₂CH₃)₂double 2-(2,4- — 144- difluorophenyl) 146 60 H OCH₃ H H O N(CH₂CH₃)₂single 3-(pyrid-4-yl) HCl 208- 1:1 220 61 H CH₃ H H O N(CH₂CH₃)₂ single3-(pyrid-4-yl) HCl 222- 1:1 225 62 H Cl H H O N(CH₂CH₃)₂ single3-(pyrid-3-yl) HCl 194- 1:1 197 63 H Cl H H O N(CH₂CH₃)₂ single2-(pyrid-3-yl) HCl 155- 1:1 157 64 H F H H O N(CH₂CH₃)₂ single2-(pyrid-4-yl) HCl 324- 1:1 326 65 H F H H O N(CH₂CH₃)₂ single3-(pyrid-4-yl) HCl 233- 1:1 242 66 H Cl H H O N(CH₂CH₃)₂ single3-(4-fluorophenyl) — 131- 132 67 H Cl H H O N(CH₂CH₃)₂ single3-(pyrid-2-yl) HCl 122- 1:1 123 68 H Cl H H O N(CH₂CH₃)₂ single2-(3-fluorophenyl) — 128- 130 69 H Cl H H O N(CH₂CH₃)₂ single3-(3-fluorophenyl) — 124- 126 70 H Br H H O N(CH₂CH₃)₂ single2-(pyrid-4-yl) HCl 300- 1:1 310 71 H Br H H O N(CH₂CH₃)₂ single3-(pyrid-4-yl) HCl 233- 1:1 238 72 H Cl H H O N(CH₂CH₃)₂ single3-(4-methylphenyl) — 155- 159 73 H Cl H H O N(CH₂CH₃)₂ single2-(4-methy(phenyl) — 118- 121 74 H Cl H H O N(CH₂CH₃)₂ single2-(2-fluorophenyl) 414* 75 H Cl H H O N(CH₂CH₃)₂ single3-(4-chlorophenyl) — 177- 178 76 H Cl H H O N(CH₂CH₃)₂ single2-(4-chlorophenyl) — 148- 149 77 H Cl H H O N(CH₂CH₃)₂ single 2-(4- —131- methoxyphenyl) 132 78 H Cl H H O N(CH₂CH₃)₂ single 3-(4- — 185-methoxyphenyl) 187 79 H Cl H H O N(CH₂CH₃)₂ double 3-(3-fluorophenyl) —142- 144 80 H Cl H H O N(CH₃)Ph single 3-(pyrid-4-yl) — 213- 215 81 H ClH H O N(CH(CH₃)₂)₂ single 2-(pyrid-4-yl) — 184- 185 82 H Cl H H ON(CH(CH₃)₂)₂ single 3-(pyrid-4-yl) — 146- 148 HCl 237- 1:1 269 83 OCH₃ HH H O N(CH₂CH₃)₂ single 3-(pyrid-4-yl) HCl 238- 1:1 240 84 H Cl H H ON(CH(CH₃)₂)₂ double 3-(pyrid-4-yl) HCl 234- 1:1 248 85 H Cl H H O

single 2-(pyrid-4-yl) HCl 1:1 153- 173 86 H Cl H H O

single 3-(pyrid-4-yl) HCl 1:1 243- 248 87 H Cl H H O N(CH(CH₃)₂)₂ single2-(pyrid-3-yl) HCl 243- 1:1 260 88 H Cl H H O N(CH(CH₃)₂)₂ single3-(pyrid-3-yl) HCl 209- 1:1 213 89 H Cl H H S N(CH(CH₃)₂)₂ single3-(pyrid-4-yl) HCl 290- 1:1 318 90 H Cl H H O

single 3-(pyrid-4-yl) HCl 1:1 228- 252 91 H Cl H H O NCH₃C(CH₃)₃ single2-(pyrid-4-yl) HCl 350- 1:1 360 92 H Cl H H O N(CH(CH₃)₂)₂ double3-(pyrid-3-yl) HCl 238- 1:1 240 93 H Cl H H O N(CH(CH₃)₂)₂ single3-(pyrid-2-yl) — 193- 195 94 H F H H O N(CH(CH₃)₂)₂ single3-(pyrid-4-yl) HCl 255- 1:1 260 95 H Cl H H O N(CH(CH₃)₂)₂ single3-(pyrid-2-yl) — 220- 222 96 H Cl H H O N(CH(CH₃)₂)₂ single2-(pyrazin-2-yl) — 175- 176 97 H F H H O N(CH(CH₃)₂)₂ double3-(pyrid-4-yl) HCl 272- 1:1 280 98 H Cl H H O N(CH(CH₃)₂)₂ double3-(pyrid-2-yl) — 213- 215 99 H Cl H H O N(CH₃)(C(CH₃)₃) single3-(pyrid-4-yl) HCl 411* 1:1 100 H Cl H H O N(CH₂CH₃)₂ double3-(pyrid-4-yl) HCl 227- 1:1 229 101 H Cl H H O N(CH₃)Ph double3-(pyrid-4-yl) HCl 248- 1:1 268 *[MH]⁺

The compounds of the invention have been subjected to pharmacologicaltests which have demonstrated their advantage as substances withtherapeutic activities.

The compounds of the invention also exhibit characteristics ofsolubility in water which promote good in vivo activity.

Study of the Binding of [³H]Ro5-4864 to Peripheral-Type BenzodiazepineReceptors (PBR or p Sites)

The affinity of the compounds of the invention for PBR or p sites (sitesof binding of peripheral type to benzodiazepines) was determined.

The p site receptors can be labelled selectively in rat kidney membranesincubated in the presence of [³H]Ro5-4864. The compounds of theinvention have formed the subject of an in vitro study with respect totheir affinity for these receptors.

The animals used are male Sprague-Dawley rats (Iffa Credo) weighing 180to 300 g. After decapitation, the kidney is removed and the tissue ishomogenized at 4° C. using a Polytron™ homogenizer for 2 min at 6/10 ofthe maximum speed in 35 volumes of 50 mM Na₂HPO₄ phosphate buffer at apH adjusted to 7.5 with NaH₂PO₄. The membrane homogenate is filteredthrough gauze and diluted tenfold with buffer.

[³H]Ro5-4864 (specific activity: 70-90 Ci/mmol; New England Nuclear), ata concentration of 0.5 nM, is incubated in the presence of 100 μl of themembrane homogenate in a final volume of 1 ml of buffer comprising thetest compound.

After incubating for 3 h at 0° C., the membranes are recovered byfiltration through Whatman GF/B™ filters washed with 2 times 4.5 ml ofcold (0° C.) incubation buffer. The amount of radioactivity retained bythe filter is measured by liquid scintigraphy.

For each concentration of studied compound, the percentage of inhibitionof the binding of [³H]Ro5-4864 is determined and then the IC₅₀concentration, the concentration which inhibits 50% of the specificbinding, is determined.

The IC₅₀ values of the most active compounds of the invention range from0.5 nM to 300 nM. In particular, compounds Nos 14, 20 and 56 in Table 2exhibit respective IC₅₀ values of 1.6 nM, 2.8 nM and 1.4 nM.

The compounds of the invention are therefore ligands with an affinityfor peripheral-type benzodiazepine receptors.

Study of the Neuroprotective Activity

Test of Survival of the Motor Neurons after Sectioning the Facial Nervein Rats Aged 4 Days

After lesion of the facial nerve in immature rats, the motor neurons ofthe facial nucleus experience neuronal death by apoptosis. Neuronalsurvival is evaluated using neuronal counting and histological methods.

Immature rats aged 4 days are anaesthetized with pentobarbital (3 mg/kgby the i.p. route). The right facial nerve is exposed and sectioned atits outlet from the stylomastoid foramen. After waking up, the youngrats are returned to their mothers and are treated for 7 days with oneor two daily administrations, by the oral or intraperitoneal route, atdoses ranging from 1 to 10 mg/kg.

7 days after the lesion, the animals are decapitated and the brains arefrozen in isopentane at −40° C. The entire facial nerve is cut with acryostat into sections with a width of 10 μm. The motor neurons arestained with cresyl violet and counted using the Histo™ software(Biocom™)

In this model, the compounds of the invention increase neuronal survivalby 38 to 78%. The results of the test of survival of the motor neuronsfor compounds Nos 14, 20 and 56 of the table are presented in Table 3below.

TABLE 3 No. 14 20 56 % increase in the survival 38% 59% 74% of theneurons (10 mg/kg po)

The results of the tests show that the most active compounds of theinvention promote neuroprotection.

The compounds of the invention can thus be used for the preparation ofmedicaments, in particular for the preparation of a medicament intendedto prevent or treat a pathology in which peripheral-type benzodiazepinereceptors are involved.

Thus, according to another of its aspects, a subject-matter of theinvention is medicaments which comprise a compound of formula (I), or anaddition salt of the latter with a pharmaceutically acceptable acid, ora hydrate or a solvate.

These medicaments are employed in therapeutics, in particular in theprevention and/or treatment of various types of peripheral neuropathies,such as traumatic or ischaemic neuropathies, infectious, alcoholic,diabetic, medicinal or genetic neuropathies, and motor neuronconditions, such as spinal amyotrophies and amyotrophic lateralsclerosis. These medicaments will also find an application in thetreatment of neurodegenerative diseases of the central nervous system,either of acute type, such as strokes and cranial and medullar traumas,or of chronic type, such as autoimmune diseases (multiple sclerosis),Alzheimer's disease, Parkinson's disease and any other disease in whichthe administration of neuroprotective/neurotrophic factors is supposedto have a therapeutic effect.

The compounds of the invention can also be used for the preparation ofmedicaments intended for the prevention and/or treatment of anxiety, ofepilepsy and of sleep disorders. This is because ligands of the PBR or psites stimulate the production of neurosteroids, such as pregnenolone,dehydroepiandrosterone and 3α-hydroxy-5α-pregnan-20-one, by promotingthe transfer of cholesterol from the outside to the inside of themitochondrial membrane. These neurosteroids modulate the activity of theGABA_(A)-chloride channel macromolecular complex and can thus produceanxiolytic, anticonvulsant and sedative activities.

The compounds of the invention can also be used in the treatment ofacute or chronic renal insufficiency, of glomerulonephritis, of diabeticnephropathy, of cardiac ischaemia and cardiac insufficiency, ofmyocardial infarction, of ischaemia of the lower limbs, of coronaryvasospasm, of angina pectoris, of pathologies associated with the heartvalves, of inflammatory heart diseases, of side effects due tocardiotoxic medicaments or as a result of heart surgery, ofatherosclerosis and of its thromboembolic complications, of restenosis,of graft rejections, or of conditions related to incorrect proliferationor incorrect migration of smooth muscle cells.

Furthermore, recent data in the literature indicate that theperipheral-type benzodiazepine receptor might play a fundamental role inthe regulation of cell proliferation and cancerization processes.Generally, and in comparison with normal tissues, an increased densityof peripheral-type benzodiazepine receptors is observed in various typesof tumours and cancers.

In human astrocytomas, the level of expression of the peripheral-typebenzodiazepine receptor is correlated with the degree of malignancy ofthe tumour, the proliferation index and the survival of the patients. Inhuman cerebral tumours, the increase in the number of peripheral-typebenzodiazepine receptors is used as a diagnostic indication in medicalimaging and as a therapeutic target for conjugates formed from a ligandof the peripheral-type benzodiazepine receptor and from a cytostaticdrug. A high density of peripheral-type benzodiazepine receptors is alsoobserved in ovarian carcinomas and breast cancers. As regards thelatter, it has been demonstrated that the level of expression of theperipheral-type benzodiazepine receptors is related to the aggressivepotential of the tumour; furthermore, the presence of a peripheral-typebenzodiazepine receptor agonist stimulates the growth of a mammarycancer line.

These combined results, which suggest a deleterious function of theperipheral-type benzodiazepine receptor in cancerization processes,constitute a relevant basis for the search for synthetic ligandsspecific for the peripheral-type benzodiazepine receptor which arecapable of blocking the effects thereof.

The compounds can therefore be used for the treatment of tumours andcancers.

The peripheral-type benzodiazepine receptors are also present in theskin and, in this respect, the compounds which can be used according tothe invention can be used for the prophylaxis or the treatment ofcutaneous stress.

The term “cutaneous stress” is understood to mean the various situationswhich might cause damage, in particular to the epidermis, whatever theagent which causes this stress. This agent can be internal and/orexternal to the body, such as a chemical or free-radical agent, or elseexternal, such as ultraviolet radiation.

Thus, the compounds which can be used according to the invention areintended to prevent and to combat cutaneous irritation, dry patches,erythemas, dysaesthetic sensations, heating sensations, pruritus of theskin and/or mucous membranes, or ageing, and can also be used incutaneous disorders, such as, for example, psoriasis, pruriginousdiseases, herpes, photodermatoses, atopic dermatitides, contactdermatitides, lichens, prurigo, pruritus, insect stings, in fibroses andother disorders of collagen maturation, in immunological disorders or indermatological conditions, such as eczema.

The compounds of the invention can also be used for the prevention andtreatment of chronic inflammatory diseases, in particular rheumatoidarthritis, and pulmonary inflammatory diseases.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundaccording to the invention. These pharmaceutical compositions comprisean effective dose of at least one compound according to the invention,or a pharmaceutically acceptable salt, a hydrate or a solvate of thesaid compound, and at least one pharmaceutically acceptable excipient.The said excipients are chosen, according to the pharmaceutical form andthe method of administration desired, from the usual excipients known toa person skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or its optional salt, solvate orhydrate, can be administered in unit administration form, as a mixturewith conventional pharmaceutical excipients, to animals and human beingsfor the prophylaxis or treatment of the above disorders or diseases.

The appropriate unit administration forms comprise oral forms, such astablets, soft or hard gelatin capsules, powders, granules and oralsolutions or suspensions, sublingual, buccal, intratracheal, intraocularand intranasal administration forms, forms for administration byinhalation, topical, transdermal, subcutaneous, intramuscular orintravenous administration forms, rectal administration forms andimplants. The compounds according to the invention can be used, fortopical application, in creams, gels, ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in the tablet form can comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscarmellose sodium  6.0 mg Maize starch 15.0 mgHydroxypropylmethylcellulose 2.25 mg Magnesium stearate  3.0 mg

The said unit forms comprise doses in order to make possible dailyadministration of 0.001 to 20 mg of active principle per kg of bodyweight, depending on the pharmaceutical dosage form.

There may be specific cases where higher or lower dosages areappropriate; such dosages do not depart from the scope of the invention.According to the usual practice, the dosage appropriate to each patientis determined by the physician according to the method of administrationand the weight and response of the said patient.

The present invention, according to another of its aspects, also relatesto a method for the treatment of the pathologies indicated above whichcomprises the administration, to a patient, of an effective dose of acompound according to the invention, or one of its pharmaceuticallyacceptable salts or hydrates or solvates.

1. A compound of formula (Va):

in which X₁, X₂, X₃ and X₄ each represent, independently of one another,a hydrogen or halogen atom or a cyano, C₁-C₆-alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy or C₁-C₆-fluoroalkoxy group; and Y represents aC₁-C₆-alkyl, C₁-C₆-fluoroalkyl, aryl or heteroaryl group; and whereinthe aryl or heteroaryl groups optionally being substituted by one ormore atoms or groups selected from halogen atoms, and C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₁-C₆-alkyl-S(O)—, C₁-C₆-alkyl-S(O)₂— andC₁-C₆-fluoroalkyl groups.
 2. A compound of formula (Vb)

in which X₁, X₂, X₃ and X₄ each represent, independently of one another,a hydrogen or halogen atom or a cyano, C₁-C₆-alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxy or C₁-C₆-fluoroalkoxy group; and Y represents an aryl orheteroaryl group; and wherein the aryl or heteroaryl groups optionallybeing substituted by one or more atoms or groups selected from halogenatoms and C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₁-C₆-alkyl-S(O)—,C₁-C₆-alkyl-S(O)₂— and C₁-C₆-fluoroalkyl groups.
 3. A method ofpreventing or treating a pathology in which peripheral-typebenzodiazepine receptors are involved, which comprises administering toa patient in need of said prevention or treatment a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof or a hydrate or a solvate thereof:

in which W represents an oxygen or sulphur atom; X₁, X₂, X₃ and X₄ eachrepresent, independently of one another, a hydrogen or halogen atom or acyano, C₁-C₆-alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxy orC₁-C₆-fluoroalkoxy group; Y is in the (N2) or (N3) position; when Y isin the (N2) position, Y represents a C₁-C₆-alkyl, C₁-C₆-fluoroalkyl,aryl or heteroaryl group; when Y is in the (N3) position, Y representsan aryl or heteroaryl group; the aryl or heteroaryl groups optionallybeing substituted by one or more atoms or groups selected from halogenatoms and C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₁-C₆-alkyl-S(O)—,C₁-C₆-alkyl-S(O)₂— and C₁-C₆— fluoroalkyl groups; the bond in the C4-C5position is a double or single bond; and R₁ and R₂ each represent,independently of one another, an aryl, benzyl or C₁-C₆-alkyl group; orelse R₁ and R₂ form, with the nitrogen atom to which they are attached,a heterocycle optionally substituted by one or more C₁-C₆-alkyl orbenzyl groups.
 4. The method according to claim 3, wherein: W representsan oxygen or sulphur atom; X₁, X₂ and X₃ each represent, independentlyof one another, a hydrogen atom, a halogen atom, a cyano group, aC₁-C₆-alkyl group or a C₁-C₆-alkoxy group; X₄ represents a hydrogenatom; Y is in the (N2) or (N3) position; when Y is in the (N2) position,Y represents a C₁-C₆-alkyl group, a C₁-C₆-fluoroalkyl group, an arylgroup or a heteroaryl group; when Y is in the (N3) position, Yrepresents an aryl group or a heteroaryl group; the aryl or heteroarylgroups optionally being substituted by one or more atoms or groupsselected from halogen atoms, C₁-C₆-alkyl groups and C₁-C₆-alkoxy groups;the bond in the C4-C5 position is a double or single bond; and R₁ and R₂each represent, independently of one another, an aryl group or aC₁-C₆-alkyl group; or else R₁ and R₂ form, with the nitrogen atom towhich they are attached, a heterocycle optionally substituted by one ortwo C₁-C₆-alkyl groups.
 5. The method according to claim 3, wherein: Wrepresents an oxygen or sulphur atom; X₁, X₂ and X₃ each represent,independently of one another, a hydrogen atom, a halogen atom, aC₁-C₆-alkyl group or a C₁-C₆-alkoxy group; X₄ represents a hydrogenatom; Y is in the (N2) or (N3) position and represents an aryl group ora heteroaryl group; the aryl or heteroaryl groups optionally beingsubstituted by one or more atoms or groups selected from halogen atoms,C₁-C₆-alkyl groups and C₁-C₆-alkoxy groups; the bond in the C4-C5position is a double or single bond; and R₁ and R₂ each represent,independently of one another, an aryl group or a C₁-C₆-alkyl group; orelse R₁ and R₂ form, with the nitrogen atom to which they are attached,a heterocycle optionally substituted by one or two C₁-C₆-alkyl groups.6. The method according to claim 3, wherein: W represents an oxygen orsulphur atom; X₁, X₂ and X₃ each represent, independently of oneanother, a hydrogen atom, a halogen atom, a C₁-C₆-alkyl group or aC₁-C₆-alkoxy group; X₄ represents a hydrogen atom; Y is in the (N3)position and represents an aryl group or a heteroaryl group; the aryl orheteroaryl groups optionally being substituted by one or more atoms orgroups selected from halogen atoms, C₁-C₆-alkyl groups and C₁-C₆-alkoxygroups; the bond in the C4-C5 position is a double or single bond; andR₁ and R₂ each represent, independently of one another, an aryl group ora C₁-C₆-alkyl group; or else R₁ and R₂ form, with the nitrogen atom towhich they are attached, a heterocycle optionally substituted by one ortwo C₁-C₆-alkyl groups.
 7. The method according to claim 3, wherein thecompound is selected from the group consisting of:7-Fluoro-2-(4-fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Fluoro-2-(4-fluorophenyl)-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]-indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN,N-diethylcarbamate hydrochloride;8-Methoxy-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride;2-(4-Methylphenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-dimethylcarbamate;2-(4-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;2-(3-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylmorpholine-4-carboxylate;2-(3-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-dimethylcarbamate;2-(3-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;2-(3-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylpyrrolidine-1-carboxylate;2-(3-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diisopropylcarbamate; 2-Phenyl-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-phenyl-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;2-(3-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN-methyl-N-phenylcarbamate;2-(2-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate; 2-Ethyl-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate; 2-Ethyl-4,5-dihydro-2H-benzo[e]indazol-1-ylN-methyl-N-phenylcarbamate;2-(2,2′,2″-Trifluoroethyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN-methyl-N-phenylcarbamate;2-(4-Fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;2-(4-Fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diisopropylcarbamate;2-(4-Fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN-methyl-N-phenylcarbamate;2-(4-Fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylpyrrolidine-1-carboxylate;2-(4-Fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylpiperidine-1-carboxylate;2-(4-Fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylmorpholine-4-carboxylate;2-(4-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-dimethylcarbamate;2-(4-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diisopropylcarbamate;2-(4-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN-methyl-N-phenylcarbamate;2-(4-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylpyrrolidine-1-carboxylate;2-(4-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylpiperidine-1-carboxylate;2-(4-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylmorpholine-4-carboxylate;2-(4-Chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl4-methylpiperazine-1-carboxylate;2-(4-Fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-dimethylcarbamate;2-(4-Fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-yl4-methylpiperazine-1-carboxylate;2-Phenyl-4,5-dihydro-2H-benzo[e]indazol-1-yl N,N-dimethylcarbamate;2-Phenyl-4,5-dihydro-2H-benzo[e]indazol-1-yl N,N-diisopropylcarbamate;2-Phenyl-4,5-dihydro-2H-benzo[e]indazol-1-yl N-methyl-N-phenylcarbamate;2-Phenyl-4,5-dihydro-2H-benzo[e]indazol-1-yl pyrrolidine-1-carboxylate;7-Chloro-2-(4-fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;2-(4-Fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN-methyl-N-propylcarbamate;2-(3-Chloro-4-methylphenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;2-(3-Chloro-4-fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(3-chloro-4-methylphenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(2,4-difluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;2-(Pyridin-4-yl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Chloro-2-(pyridin-2-yl)-4,5-dihydro-2H-benzo[e]-indazol-1-ylN,N-diethylcarbamate;7-Methoxy-2-(4-fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Bromo-2-(4-fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(3-chloro-4-fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-methyl-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate; 2-(3-Chlorophenyl)-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate; 2-(4-Fluorophenyl)-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate; 2-(4-Fluorophenyl)-2H-benzo[e]indazol-1-ylN-methyl-N-propylcarbamate;2-(3-Chloro-4-fluorophenyl)-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;2-(3-Chloro-4-methylphenyl)-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(4-fluorophenyl)-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(3-chloro-4-fluorophenyl)-2H-benzo[e]-indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(3-chloro-4-methylphenyl)-2H-benzo[e]-indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(2,4-difluorophenyl)-2H-benzo[e]-indazol-1-ylN,N-diethylcarbamate;7-Methoxy-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Methyl-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Chloro-3-(pyridin-3-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Chloro-2-(pyridin-3-yl)-4,5-dihydro-2H-benzo[e]-indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Fluoro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]-indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Fluoro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Chloro-3-(4-fluorophenyl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-3-(pyridin-2-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Chloro-2-(3-fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-3-(3-fluorophenyl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Bromo-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]-indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Bromo-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Chloro-3-(4-methylphenyl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(4-methylphenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(2-fluorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-3-(4-chlorophenyl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(4-chlorophenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-2-(4-methoxyphenyl)-4,5-dihydro-2H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-3-(4-methoxyphenyl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-3-(3-fluorophenyl)-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate;7-Chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN-methyl-N-phenylcarbamate;7-Chloro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]-indazol-1-ylN,N-diisopropylcarbamate;7-Chloro-4,5-dihydro-3-(pyridin-4-yl)-3H-benzo[e]-indazol-1-ylN,N-diisopropylcarbamate hydrochloride;6-Methoxy-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diethylcarbamate hydrochloride;7-Chloro-3-(pyridin-4-yl)-3H-benzo[e]indazol-1-ylN,N-diisopropylcarbamate hydrochloride;7-Chloro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]-indazol-1-ylpiperidine-1-carboxylate hydrochloride;7-Chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylpiperidine-1-carboxylate hydrochloride;7-Chloro-2-(pyridin-3-yl)-4,5-dihydro-2H-benzo[e]-indazol-1-ylN,N-diisopropylcarbamate hydrochloride;7-Chloro-3-(pyridin-3-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN,N-diisopropylcarbamate hydrochloride;7-Chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN,N-diisopropylthiocarbamate hydro-chloride;7-Chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylcis-2,6-dimethylpiperidine-1-carboxylate hydrochloride;7-Chloro-2-(pyridin-4-yl)-4,5-dihydro-2H-benzo[e]-indazol-1-ylN-methyl-N-(tert-butyl)carbamate hydrochloride;7-Chloro-3-(pyridin-3-yl)-3H-benzo[e]indazol-1-ylN,N-diisopropylcarbamate hydrochloride;7-Chloro-3-(pyridin-2-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN,N-diisopropylcarbamate;7-Fluoro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN,N-diisopropylcarbamate hydro-chloride;7-Chloro-3-(pyrimidin-2-yl)-4,5-dihydro-3H-benzo[e]indazol-1-ylN,N-diisopropylcarbamate;7-Chloro-2-(pyrazin-2-yl)-4,5-dihydro-2H-benzo[e]-indazol-1-ylN,N-diisopropylcarbamate;7-Fluoro-3-(pyridin-4-yl)-3H-benzo[e]indazol-1-ylN,N-diisopropylcarbamate hydrochloride;7-Chloro-3-(pyridin-2-yl)-3H-benzo[e]indazol-1-ylN,N-diisopropylcarbamate;7-Chloro-3-(pyridin-4-yl)-4,5-dihydro-3H-benzo[e]-indazol-1-ylN-methyl-N-(tert-butyl)carbamate hydrochloride;7-Chloro-3-(pyridin-4-yl)-3H-benzo[e]indazol-1-yl N,N-diethylcarbamatehydrochloride; and 7-Chloro-3-(pyridin-4-yl)-3H-benzo[e]indazol-1-ylN-methyl-N-phenylcarbamate hydrochloride.
 8. The method according toclaim 3, wherein said pathology is selected from peripheralneuropathies, motor neuron conditions, neurodegenerative diseases of thecentral nervous system, anxiety, epilepsy, sleep disorders, acute orchronic renal insufficiency, glomerulonephritis, diabetic nephropathy,cardiac ischaemia and cardiac insufficiency, myocardial infarction,ischaemia of the lower limbs, coronary vasospasm, angina pectoris,pathologies associated with the heart valves, inflammatory heartdiseases, side effects due to cardiotoxic medicaments or as a result ofheart surgery, atherosclerosis and its thromboembolic complications,restenosis, graft rejections, conditions related to incorrectproliferation or incorrect migration of smooth muscle cells, tumours andcancers, cutaneous stress, chronic inflammatory diseases, and pulmonaryinflammatory diseases.
 9. The method according to claim 8, wherein saidperipheral neuropathies are chosen from traumatic or ischaemicneuropathies or infectious, alcoholic, diabetic, medicinal or geneticneuropathies.
 10. The method according to claim 8, wherein said motorneuron conditions are chosen from spinal amyotrophies and amyotrophiclateral sclerosis.
 11. The method according to claim 8, wherein saidneurodegenerative diseases of the central nervous system are chosen fromstrokes, cranial and medullar traumas, multiple sclerosis, Alzheimer'sdisease or Parkinson's disease.
 12. The method according to claim 9,wherein said peripheral neuropathies are traumatic or ischaemicneuropathies.
 13. The method according to claim 9, wherein saidperipheral neuropathies are infectious, alcoholic, diabetic, medicinalor genetic neuropathies.
 14. The method according to claim 9, whereinsaid peripheral neuropathies is diabetic neuropathies.
 15. The methodaccording to claim 3, wherein said pathology is diabetic peripheralneuropathy.
 16. The method according to claim 7, wherein said pathologyis diabetic peripheral neuropathy.
 17. The method according to claim 3,wherein said pathology is chemotherapy induced neuropathy.
 18. Themethod according to claim 7, wherein said pathology is chemotherapyinduced neuropathy.
 19. The method according to claim 8, wherein saidchronic inflammatory disease is rheumatoid arthritis.